The goal of this project is to study the role of the glial derived neurotrophic factor (GDNF) in alcohol addiction. Previous evidence suggests that activation of the GDNF pathway can reverse biochemical and behavioral adaptations to drugs of abuse. We found that the naturally occurring alkaloid Ibogaine, that possesses anti-addiction properties for drugs of abuse and alcohol, activates the GDNF pathway in vitro and in vivo. We further found that mutant mice that express 50% of the GDNF message consume more ethanol than their corresponding wild-type controls. Curiously, we also found that acute exposure of cells to ethanol, like GDNF or Ibogaine, induces the phosphorylation of the GDNF receptor tyrosine kinase, Ret, whereas chronic exposure to ethanol reduces the protein level of Ret. Based on these results we hypothesize that, acutely, ethanol activates the GDNF pathway as a homeostatic pathway that prevents or delays the development of neuroadaptations leading to addiction. We further hypothesize that when this homeostatic mechanism ceases functioning, the initiation of long-term molecular and morphological changes that lead to behaviors associated with the development of addiction occur. Using biochemical and behavioral approaches, this proposal will address both hypotheses. In specific aim 1, we will test the hypothesis that the GDNF pathway is activated upon acute treatment of cells or mice with ethanol, and identify the mechanism by which acute ethanol induces the phosphorylation of the GDNF receptor Ret. In specific aim 2, we will test the hypothesis that long-term ethanol treatment inhibits the GDNF pathway and we will identify the biochemical consequences of this inhibition. In specific aim 3, we will test the hypothesis that activation of the GDNF pathway will reduce whereas inhibition of the GDNF pathway will enhance the reinforcing activities of ethanol in ethanol self-administration and relapse models. Our long-term goal is understand the function of growth factors such as GDNF in alcohol addiction. The information generated from these studies may elucidate novel pathways for the delay or prevention of adaptations to chronic alcohol and may lead to the development of new approaches for the treatment of alcohol addiction.